Pharmaceutical compositions and methods for treating mental, behavioral, cognitive disorders

ABSTRACT

A pharmaceutical composition containing the therapeutically active ingredients of azelastine or a pharmaceutically acceptable salt of azelastine and memantine or a pharmaceutically acceptable salt of memantine is disclosed. A method of using the pharmaceutical composition for treating patients suffering from mental, behavioral, cognitive disorders is also disclosed.

FIELD OF THE INVENTION

The invention relates to the field of practical medicine, namely, to thecombined use of pharmaceutical compositions exhibiting a neurotropicaction, alleviating manifestations of mental, behavioral, cognitivedisorders in cases of organic damage of various origin to the centralnervous system.

BACKGROUND OF THE INVENTION

Alzheimer's disease (AD) is a progressive, chronic neurodegenerativedisease that usually starts slowly and gradually worsens over time.Alzheimer's is the most common cause of dementia among older adults.Dementia is the loss of cognitive functioning—thinking, remembering, andreasoning—and behavioral abilities to such an extent that it interfereswith a person's daily life and activities. In its early stages, memoryloss is mild, but with late-stage AD, individuals lose the ability tocarry on a conversation and respond to their environment. If untreated,AD ultimately leads to death. Although the speed of progression canvary, the typical life expectancy following diagnosis is three to nineyears.

A central mechanism in learning and memory is long-term potentiation(LTP). LTP is mediated by the neurotransmitter glutamate via the NMDAreceptor. The NMDA receptors can be found diffusely throughout thebrain. However, they densely populate the dendrites of pyramidal cellsin the hippocampus and cortex (areas known to be involved in cognition,learning, and memory). In addition to the relationship between LTP andlearning, elevated glutamate levels are associated with excitotoxicity.Chronic low-dose administration of NMDA receptor agonists has been shownto induce apoptosis, while high doses induce necrosis. The activation ofglutamate receptors has also been found to induce the release ofglutamate. Thus, a large build-up of glutamate can occur and induce amassive accumulation of Ca2+, leading to apoptosis. It was also notedthat amyloid-beta (AB) plaques increase a neuron's vulnerability toexcitotoxicity. AB plaques, a pathological feature of AD, were found toinduce depolarization of astrocytes, extracellular accumulation ofglutamate, and intracellular deposition of Ca2+. Therefore, theglutamate-induced excitotoxicity pathway made an excellent target forthe therapy of AD.

Under physiologic conditions, the glutamate released by neurons ismetabolized or taken up by neighboring cells. When these pathways aredisrupted, the accumulated glutamate overexcites the NMDA receptor andinduces pathology characteristic of neurodegenerative diseases. NMDAreceptors act as a calcium [II] ion (Ca2+) channel that activates whenbound by glycine, glutamate, and/or NMDA. However, the channel functionsonly when the cell membrane is depolarized due to the blockade of thechannel by the magnesium [II] ion (Mg2+). This prevents the influx ofCa2+ when the neuron is at rest. Under pathological conditions, such asa chronically depolarized membrane, Mg2+ leaves the channel and neuronalmetabolism is inhibited, leading to cell death. When this happens, theCa2+ influx is unrestricted for a longer period of time than normal.This influx of Ca2+ contributes to an alteration of cell function,leading to cell death either through free radicals or through overloadof the mitochondria, resulting in free radical formation, caspaseactivation, and the release of apoptosis-inducing factors. Antagoniststo the NMDA vary in affinity and in site of action, resulting indifferent alterations to the channel. Regardless of the mechanism ofaction, antagonists decrease the permeability of the channel and preventan influx of Ca2+. Thus, NMDA receptor antagonists are looked to aspossible neuroprotective agents and potential therapies forneurodegenerative disease.

Most NMDA antagonists are competitive antagonists and are not welltolerated by patients due to side effects, which can includehallucinations and schizophrenia-type symptoms. The side effects likelyresult from the competitive antagonists blocking physiological functionsof the NMDA receptor. Its role in cognition, memory, and learning makeit necessary that any drug using the NMDA receptor as a target of actionmust preserve physiologic function to be therapeutically useful.Memantine acts on activated NMDA receptors by binding to a site locatedin the channel of the receptor.

Memantine is a fast-binding antagonist which binds to the channel in apseudo-first order manner. However, it also dissociates from thereceptor quickly and in a concentration independent manner. This allowsthe dose to affect the binding of memantine without affecting itsremoval from the site of action and allowing for increased potency withminimal side effects. In comparison with other antagonists, memantinehas a much faster course of action and thus has less effect onphysiologic mechanisms. For this reason, memantine offers a lot ofpromise in the therapy of neurodegenerative disease because it willpreserve physiological function. In addition, the uncompetitive natureof memantine's mechanism of action makes its antagonistic activity morepotent in areas with massive activation of NMDA receptors. Memantine'smechanism of action is also voltage-dependent, which leads to theremoval of the memantine blockage by depolarization of the membrane. Allof these characteristics make memantine a strong candidate for treatingpathology induced by excitotoxicity. In several studies, memantine wasfound to prevent neuronal death induced via excitotoxic mechanisms.

However, memantine will not cure AD or prevent the loss of theseabilities at some time in the future. So, AD has no current cure, andour effort is to find better ways to reverse the disease, delay andprevent it from developing.

On the other hand, the genetic, cellular, and molecular changesassociated with AD support the evidence that activated immune andinflammatory processes is a part of the disease. Also, a strong benefitof long-term use of NSAIDs was shown in epidemiological studies. So, itis generally accepted that AD is partially an inflammatory disease andthat inhibiting inflammation is an option of treating AD.

Inflammation clearly occurs in pathologically vulnerable regions of theAD brain, and it does so with the full complexity of local peripheralinflammatory responses. In the periphery, degenerating tissue and thedeposition of highly insoluble abnormal materials are classicalstimulants of inflammation. Likewise, in the AD brain damaged neuronsand neurites and highly insoluble amyloid β peptide deposits andneurofibrillary tangles provide obvious stimuli for inflammation.Because these stimuli are discrete, micro-localized, and present fromearly preclinical to terminal stages of AD, local upregulation ofcomplement, cytokines, acute phase reactants, and other inflammatorymediators is also discrete, micro-localized, and chronic. Cumulated overmany years, direct and bystander damage from AD inflammatory mechanismsis likely to significantly exacerbate the very pathogenic processes thatgave rise to it. Thus, animal models and clinical studies so farstrongly suggest that AD inflammation significantly contributes to ADpathogenesis. By better understanding AD inflammatory andimmune-regulatory processes, it should be possible to developanti-inflammatory approaches that may reverse or delay or preventdeveloping of this devastating disorder.

Azelastine is classified pharmacologically as a second generationantihistamine and is a relatively selective, non-sedating, competitiveantagonist at H1 receptors. More uniquely, its inhibition ofinflammatory mediators, in addition to antihistaminic and mast cellstabilizing effects, places it among the new generation of dual-actinganti-inflammatory drugs. In addition to azelastine's high affinity forH1 receptors, its ability to modify several other mediators ofinflammation and allergy contributes to its mechanism of action. Invitro and in vivo studies, as well as clinical trials support the dualeffects of direct inhibition and stabilization of inflammatory cells. Invitro data indicate that azelastine's affinity for H1 receptors isestimated to be several times greater than that of chlorpheniramine, afirst-generation H1 antagonist. Azelastine has only weak affinity for H2receptors. Release of histamine from mast cells is also inhibitedpossibly by reversible inhibition of voltage-dependent L-type calciumchannels. Inhibition of mast cell degranulation may also decrease therelease of other inflammatory mediators, including leukotrienes andinterleukin-1β, among others. Azelastine also directly antagonizes othermediators of inflammation, such as tumor necrosis factor-α,leukotrienes, endothelin-1, and platelet-activating factor.

SUMMARY OF THE INVENTION

The present invention includes a pharmaceutical composition thatcomprises two active ingredients and one or more pharmaceuticallyacceptable excipients. This pharmaceutical composition comprises thefirst active ingredient that is azelastine or a pharmaceuticallyacceptable salt of azelastine and the second active ingredient that ismemantine or a pharmaceutically acceptable salt of memantine.

In some embodiments of this invention, the pharmaceutically acceptablesalt of azelastine in the pharmaceutical composition is azelastinehydrochloride and the pharmaceutically acceptable salt of memantine inthis pharmaceutical composition is memantine hydrochloride.

In some embodiments of this invention, azelastine hydrochloride (and/orother salt thereof) in the pharmaceutical composition is provided in anamount of about 1 mg to about 20 mg and/or memantine hydrochloride(and/or other salt thereof) in this pharmaceutical composition is in anamount of about 1 mg to about 30 mg.

The present invention also includes an oral pharmaceutical dosage formof the pharmaceutical composition that is a solid form or a liquid form.

The present invention further includes the medical use of the oralpharmaceutical dosage form of the pharmaceutical composition throughadministration of the dosage form to patients with a neurodegenerativedisorder such as Alzheimer's disease, vascular dementia, or Parkinson'sdisease.

In some embodiments of this invention, an oral pharmaceutical dosageform of the pharmaceutical composition containing azelastinehydrochloride (and/or other salt thereof) in an amount of about 6 mg toabout 12 mg and/or memantine hydrochloride (and/or other salt thereof)of in an amount of about 2 mg to about 6 mg is administered to patientswith late stage Alzheimer's disease

DETAILED DESCRIPTION OF THE INVENTION

The inventors of the present invention surprisingly found that apharmaceutical composition with an oral dosage form comprising theactive agents, a salt form of azelastine and a salt form of memantine,is suitable for treating patients suffering from mental, behavioral,cognitive disorders.

The detailed description provided below is intended as a description ofthe present examples and is not intended to represent the only forms inwhich the present example may be constructed or utilized. Thedescription sets forth the functions of the example and the sequence ofsteps for constructing and operating the example. However, the same orequivalent functions and sequences may be accomplished by differentexamples.

Definitions

As used in the present specification, the following words and phrasesare generally intended to have the meanings as set forth below, exceptto the extent that the context in which they are used indicatesotherwise.

Mental, behavioral, cognitive disorders can include but are not limitedto Alzheimer's disease, dementia, Parkinson's disease, Huntington'sdisease and combinations of any thereof and other neurodegenerativedisorders.

As used herein, the term “memantine” refers to memantine free base,1-Amino-3,5-dimethyladamantane, 1,3-Dimethyl-5-adamantanamine,3,5-Dimethyl-1-adamantanamine, or3,5-Dimethyltricyclo(3.3.1.1(3,7))decan-1-amine. In certain embodiments,memantine also includes any pharmaceutically acceptable salt, such asthe hydrochloride or HCl salt. Preferably, in any embodiments of theinvention as described herein, the memantine is in the form of itshydrochloride salt, as memantine hydrochloride or memantine HCl. Morepreferably, in any embodiment of the invention as described herein,reference to the amounts and dosage ranges of memantine in oral dosageforms are to the amounts and dosage ranges of memantine hydrochloride.

As used herein, the term “azelastine” refers to azelastine free base, or4-(p-Chlorobenzyl)-2-(hexahydro-1-methyl-1H-azepin-4-yl)-1-(2H)-phthalazinone.In certain embodiments, azelastine also includes any pharmaceuticallyacceptable salt, such as the hydrochloride or HCl salt. Preferably, inany embodiments of the invention as described herein, azelastine is inthe form of its hydrochloride salt, as azelastine hydrochloride orazelastine HCl. More preferably, in any embodiment of the invention asdescribed herein, reference to the amounts and dosage ranges ofazelastine in the solid oral dosage forms are to the amounts and dosageranges of azelastine hydrochloride.

As used herein, “treating” or “treatment” means complete cure orincomplete cure, or it means that the symptoms of the underlying diseaseor associated conditions are at least reduced and/or delayed, and/orthat one or more of the underlying cellular, physiological, orbiochemical causes or mechanisms causing the symptoms are reduced,delayed and/or eliminated. It is understood that reduced or delayed, asused in this context, means relative to the state of the untreateddisease, including the molecular state of the untreated disease, notjust the physiological state of the untreated disease.

The term “effective amount” refers to an amount that is sufficient toeffect treatment, as defined below, when administered to a mammal inneed of such treatment. The therapeutically effective amount will varydepending upon the patient being treated, the weight and age of thepatient, the severity of the disease condition, the manner ofadministration and the like, which can readily be determined by one ofordinary skill in the art. The pharmaceutical compositions may beadministered in either single or multiple doses by oral administration.Administration may be via capsule, tablet, or the like.

The term “about” used herein in the context of quantitative measurementsmeans the indicated amount ±10%. For example, with a ±10% range, “about5 mg” can mean 4.5-5.5 mg.

The pharmaceutical composition may be formulated for pharmaceutical useusing methods known in the art, for example, Ansel's PharmaceuticalDosage Forms and Drug Delivery Systems Tenth (by Loyd Allen, 2013) andHandbook of Pharmaceutical Manufacturing Formulations (Volumes 1-6 bySarfaraz K. Niazi). Accordingly, incorporation of the active compoundsand a controlled, or slow release matrix may be implemented.

Either fluid or solid unit dosage forms can be readily prepared for oraladministration. For example, admixed with conventional ingredients suchas dicalcium phosphate, magnesium aluminum silicate, magnesium stearate,calcium sulfate, starch, talc, lactose, acacia, methyl cellulose andfunctionally similar materials as pharmaceutical excipients or carriers.A sustained release formulation may optionally be used. In older orincoherent subjects sustained release formulations may even bepreferred. Capsules may be formulated by mixing the compound with apharmaceutical diluent which is inert and inserting this mixture into ahard gelatin capsule having the appropriate size. If soft capsules aredesired, a slurry of the compound with an acceptable vegetable, lightpetroleum or other inert oil can be encapsulated by forming into agelatin capsule.

Suspensions, syrups and elixirs may be used for oral administration orfluid unit dosage forms. A fluid preparation including oil may be usedfor oil soluble forms. A vegetable oil such as corn oil, peanut oil or aflower oil, for example, together with flavoring agents, sweeteners andany preservatives produces an acceptable fluid preparation. A surfactantmay be added to water to form a syrup for fluid unit dosages.Hydro-alcoholic pharmaceutical preparations may be used having anacceptable sweetener, such as sugar, saccharin or a biological sweetenerand a flavoring agent in the form of an elixir.

The solid oral dosage formulation of this disclosure means a form oftablets, caplets, bi-layer tablets, film-coated tablets, pills,capsules, or the like. Tablets in accordance with this disclosure can beprepared by any mixing and tableting techniques that are well known inthe pharmaceutical formulation industry. In some examples, the dosageformulation is fabricated by direct compressing the respectivelyprepared sustained-release portion and the immediate-release portion bypunches and dies fitted to a rotary tableting press, ejection orcompression molding or granulation followed by compression.

The pharmaceutical compositions provided in accordance with the presentdisclosure are usually administered orally. This disclosure thereforeprovides pharmaceutical compositions that comprise a solid dispersioncomprising azelastine and memantine as described herein and one or morepharmaceutically acceptable excipients or carriers including but notlimited to, inert solid diluents and fillers, diluents, includingsterile aqueous solution and various organic solvents, permeationenhancers, solubilizers, disintegrants, lubricants, binders, glidants,adjuvants, and combinations thereof. Such compositions are prepared in amanner well known in the pharmaceutical arts (see, e.g., Ansel'sPharmaceutical Dosage Forms and Drug Delivery Systems, Tenth (by LoydAllen, 2013) and Handbook of Pharmaceutical Manufacturing Formulations(Volumes 1-6 by Sarfaraz K. Niazi)).

The pharmaceutical composition may further comprise pharmaceuticalexcipients such as diluents, binders, fillers, glidants, disintegrants,lubricants, solubilizers, and combinations thereof. Some examples ofsuitable excipients are described herein. When the pharmaceuticalcomposition is formulated into a tablet, the tablet may be uncoated ormay be coated by known techniques including microencapsulation to delaydisintegration and adsorption in the gastrointestinal tract and therebyprovide a sustained action over a longer period. For example, a timedelay material such as glyceryl monostearate or glyceryl distearatealone or with a wax may be employed.

In embodiments, the pharmaceutical composition can comprise a) about 1mg-50 mg of azelastine HCl (and/or other salt thereof) and/or b) about 1mg to 70 mg of memantine HCl (and/or other salt thereof) or a) about 2mg-20 mg of azelastine HCl (and/or other salt thereof) and/or b) about 2mg to 30 mg of memantine HCl (and/or other salt thereof) or a) about 8mg-16 mg of azelastine HCl (and/or other salt thereof) and/or b) about 2mg to 5 mg of memantine HCl (and/or other salt thereof). For example,the composition can comprise a) about 12 mg of azelastine HCl (and/orother salt thereof) and/or b) about 3 mg of memantine HCl (and/or othersalt thereof). Further, for example, compositions of the invention cancomprise azelastine or a pharmaceutically acceptable salt of azelastinepresent in an amount in the range of about 1 mg to about 50 mg and/ormemantine or a pharmaceutically acceptable salt of memantine present inan amount in the range of about 1 mg to about 70 mg. In embodiments, theamount of azelastine HCl (and/or other salt thereof) present in thecomposition can be equal to, more than, or less than the amount ofmemantine HCl (and/or other salt thereof) present in the composition. Inembodiments, the amount of azelastine HCl (and/or other salt thereof)present in the composition can be 2 times as much, or 3 times as much,or 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 75, 100, or1,000 times as much as the amount of memantine HCl (and/or other saltthereof) present in the composition, or vice versa. Any one or more ofthe compositions of the invention can be used with any one or more themethods of the invention disclosed herein, or other methods of using thecompositions.

It will be understood, that the amount of the pharmaceutical compositioncontaining azelastine HCl and memantine HCl actually administeredusually will be determined by a physician, in the light of the relevantcircumstances, including the condition to be treated, the chosen routeof administration, the actual compound administered and its relativeactivity, the age, weight and response of the individual patient, theseverity of the patient's symptoms, and the like.

The pharmaceutical compositions, pharmaceutical dosage forms, andtablets containing azelastine HCl and memantine HCl as described hereinare administered to a patient suffering from a neurodegenerativedisorder, such as Alzheimer's disease, by oral administration oncedaily, twice daily, once every other day, two times a week, three timesa week, four times a week, or five times a week.

In embodiments, the pharmaceutical dosage forms and tablets ofpharmaceutical compositions containing azelastine HCl and memantine HClas described herein are effective in reversing symptoms in patients withlate stage Alzheimer's disease in about 6-24 weeks.

The following Examples are illustrative and should not be interpreted tolimit the scope of the claimed subject matter.

Example 1

A 79 year old female with a weight of 51 kilograms was diagnosed withlate stage Alzheimer's disease and treated with memantine (10 mg) for 5years. But her memory and cognitive skills continued to worsen. Shecould barely remember anything and could only speak a few words. Sheeventually had a round-the-clock assistance with her daily activitiesand personal caring. She couldn't walk for more than 10 steps even withassistance. At this stage, she started a treatment with liquid oral formof the claimed pharmaceutical composition containing 12 mg of azelastineHCl and 5 mg of memantine HCl once daily. After only a month and half,with assistance she could walk. After 3 months, she had facial and eyeexpression and could talk for a few minutes and walked with only lightassistance. After 6 months of the treatment, she could talk freely andsang songs and could walk independently. During the 6-month treatment,her weight increased by 5 kilograms.

Example 2

An 81 year old female with a weight of 55 kilograms was diagnosed withlate stage Alzheimer's disease. She had a round-the-clock assistancewith her daily activities including personal care, eating, walking. Shecould only speak less than 5 words and had an irregular sleepingpattern. She was treated with a liquid oral form of the claimedpharmaceutical composition containing 12 mg of azelastine HCl and 5 mgof memantine HCl. After only a month and half, her round-the-clockassistance was reduced by around 50%. After 3 months, she could carryout her basic personal care activities herself and could speak more than10 words.

Example 3

A 77 year old male with a weight of 66 kilograms was diagnosed with latestage Alzheimer's disease. He could only speak a few words. He haddifficulty in sleeping. His personality was described as illogical orirrational, anxious or irritable, and aggressive or hostile. He wasuncooperative most of time. He needed light assistance with walking. Hewas monitored by an assistant round-the-clock. He was treated withtablets of the pharmaceutical composition containing 14 mg of azelastineHCl and 5 mg of memantine HCl. After a month and half, his personalitywas described as more rational, with much less aggression with nohostility. After 3 months, he could sleep regularly and he no longerneeded round-the-clock assistance. He could speak for more than 1minute.

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The present invention has been described with reference to particularembodiments having various features. In light of the disclosure providedabove, it will be apparent to those skilled in the art that variousmodifications and variations can be made in the practice of the presentinvention without departing from the scope or spirit of the invention.One skilled in the art will recognize that the disclosed features may beused singularly, in any combination, or omitted based on therequirements and specifications of a given application or design. Whenan embodiment refers to “comprising” certain features, it is to beunderstood that the embodiments can alternatively “consist of” or“consist essentially of” any one or more of the features. Any of themethods disclosed herein can be used with any of the compositionsdisclosed herein or with any other compositions. Likewise, any of thedisclosed compositions can be used with any of the methods disclosedherein or with any other methods. Other embodiments of the inventionwill be apparent to those skilled in the art from consideration of thespecification and practice of the invention.

It is noted in particular that where a range of values is provided inthis specification, each value between the upper and lower limits ofthat range is also specifically disclosed. The upper and lower limits ofthese smaller ranges may independently be included or excluded in therange as well. The singular forms “a,” “an,” and “the” include pluralreferents unless the context clearly dictates otherwise. It is intendedthat the specification and examples be considered as exemplary in natureand that variations that do not depart from the essence of the inventionfall within the scope of the invention. Further, all of the referencescited in this disclosure are each individually incorporated by referenceherein in their entireties and as such are intended to provide anefficient way of supplementing the enabling disclosure of this inventionas well as provide background detailing the level of ordinary skill inthe art.

The invention claimed is:
 1. A pharmaceutical composition, comprising:about 10 mg to about 50 mg of azelastine or of a pharmaceuticallyacceptable salt of azelastine; memantine or a pharmaceuticallyacceptable salt of memantine; and one or more pharmaceuticallyacceptable excipients.
 2. The pharmaceutical composition of claim 1,wherein the azelastine or the pharmaceutically acceptable salt ofazelastine is present in the pharmaceutical composition in an amount inthe range of about 10 mg to about 20 mg.
 3. The pharmaceuticalcomposition of claim 2, wherein the pharmaceutically acceptable salt ofazelastine is azelastine hydrochloride.
 4. The pharmaceuticalcomposition of claim 1, wherein the memantine or the pharmaceuticallyacceptable salt of memantine is present in the pharmaceuticalcomposition in an amount in the range of about 1 mg to about 70 mg. 5.The pharmaceutical composition of claim 4, wherein the pharmaceuticallyacceptable salt of memantine is memantine hydrochloride.
 6. Thepharmaceutical composition of claim 5, wherein the memantinehydrochloride is present in an amount in the range of about 2 mg toabout 20 mg.
 7. The pharmaceutical composition of claim 1, wherein: theazelastine or the pharmaceutically acceptable salt of azelastine ispresent in the pharmaceutical composition in an amount in the range ofabout 10 mg to about 16 mg; and the memantine or the pharmaceuticallyacceptable salt of memantine is present in the pharmaceuticalcomposition in an amount in the range of about 1 mg to about 70 mg. 8.The pharmaceutical composition of claim 1, wherein the azelastine isazelastine hydrochloride and is present in an amount in the range ofabout 10 mg to about 16 mg.
 9. The pharmaceutical composition of claim1, wherein the pharmaceutical composition is formulated as an oralpharmaceutical dosage form.
 10. The pharmaceutical composition of claim9, wherein the oral pharmaceutical dosage form is a solid form or aliquid form.
 11. The pharmaceutical composition of claim 1, wherein: theazelastine or the pharmaceutically acceptable salt of azelastine ispresent in the pharmaceutical composition in an amount that is 2, 3, 4,5, 6, 7, 8, 9, or 10 times as much as the memantine or thepharmaceutically acceptable salt of memantine; or the memantine or thepharmaceutically acceptable salt of memantine is present in thepharmaceutical composition in an amount that is 2, 3, 4, 5, 6, 7, 8, 9,or 10 times as much as the azelastine or the pharmaceutically acceptablesalt of azelastine.
 12. A method comprising: administering apharmaceutical composition to a patient having Alzheimer's disease,wherein the pharmaceutical composition comprises: about 10-50 mg ofazelastine or of a pharmaceutically acceptable salt of azelastine;memantine or a pharmaceutically acceptable salt of memantine; and one ormore pharmaceutically acceptable excipients.
 13. The method of claim 12,wherein the pharmaceutical composition is administered daily to thepatient in an oral solid or liquid form.
 14. The method of claim 13,wherein the azelastine or the pharmaceutically acceptable salt ofazelastine is present in the pharmaceutical composition in an amount inthe range of about 10 mg to about 20 mg daily.
 15. The method of claim13, wherein the memantine or the pharmaceutically acceptable salt ofmemantine is present in the pharmaceutical composition in an amount inthe range of about 1 mg to about 70 mg.
 16. The method of claim 12,wherein: the azelastine or the pharmaceutically acceptable salt ofazelastine is present in the pharmaceutical composition in an amount inthe range of about 10 mg to about 20 mg; and the memantine or thepharmaceutically acceptable salt of memantine is present in thepharmaceutical composition in an amount in the range of about 1 mg toabout 70 mg.
 17. The method of claim 12, further comprisingadministering the pharmaceutical composition to the patient daily andfor a period of at least twelve weeks.
 18. The method of claim 12,wherein the pharmaceutical composition comprises about 12 mg to about 20mg of the azelastine or a pharmaceutically acceptable salt ofazelastine.
 19. The method of claim 18, wherein the memantine or apharmaceutically acceptable salt of thereof is present in thepharmaceutical composition in an amount in the range of about 1 mg toabout 70 mg.
 20. The method of claim 12, wherein: the azelastine or thepharmaceutically acceptable salt of azelastine is present in thepharmaceutical composition in an amount that is 2, 3, 4, 5, 6, 7, 8, 9,or 10 times as much as the memantine or the pharmaceutically acceptablesalt of memantine; or the memantine or the pharmaceutically acceptablesalt of memantine is present in the pharmaceutical composition in anamount that is 2, 3, 4, 5, 6, 7, 8, 9, or 10 times as much as theazelastine or the pharmaceutically acceptable salt of azelastine.